Intermediates for producing enyne derivatives

ABSTRACT

A compound of the formula: ##STR1## wherein R 11  is hydrogen, lower alkyl, haloloweralkyl, lower alkenyl, lower alkynyl or cycloalkyl; R 21  is a group of the formula: ##STR2## wherein each of R 3 , R 31 , and R 32  which may be the same or different, is hydrogen or lower alkyl, each of R 4 , R 5 , R 41  and R 51 , which may be the same or different, is hydrogen, halogen, hydroxyl, lower alkyl or lower alkoxy, R 42  is hydroxyl, halogen, R 8  --O--, or R 6  --X--Y-- wherein R 6  is phenyl or thienyl which may have one or two substituents each of X and Y, which may be the same or different, is oxygen, sulfur, carbonyl, --CHR 8  -- or --NR b , or X and Y together form a vinylene group or an ethynylene group, provided that when either one of X and Y is oxygen, sulfur or --NR b , the other is carbonyl or --CHR a , and R 7  is lower alkyl or cycloalkyl which may be substituted by hydroxy or lower alkoxy, phenyl or tri-lower alkylsilyl; and W is chlorine or bromine.

This is a division, of Ser. No. 07/974,488, filed Nov. 12, 1992, nowU.S. Pat. No. 5,296,612, which is a divisional application of Ser. No.07/861,160, filed Mar. 27, 1992 which is now U.S. Pat. No. 5,231,183,which is a continuation of Ser. No. 07/588,931, filed Sep. 27, 1990 nowabandoned.

The present invention relates to a novel process for producing enynederivatives. More particularly, it relates to a process for producingenyne derivatives which are useful for the preparation of compoundsshowing strong inhibiting activities against squalene.epoxidase ofEumycetes and thus being useful as anti-Eumycetes agents (typicalexample being Terbinafine: J. Med. Chem, 27, 1539 (1984)), compoundsselectively inhibiting squalene.epoxidase of mammals and having stronganti-cholesterol activities (substituted alkyl amine derivatives;Japanese Patent Application No. 296840/1988) and their precursors.

Heretofore, the following methods have been known for the preparation ofacetylene-conjugated allylamine derivatives. J. Med. Chem., 27, 1539(1984) and Tetrahedron, 41, 5685 (1985) disclose a method for producingan acetylene-conjugated (E)-allylamine derivative by reducing with Dibal(diisobutylaluminum hydride) a conjugated 1,3-diynyl amine obtainable bycoupling a terminal acetylene of a propargyl amine derivative with abromoacetylene in the presence of copper chloride, or by subjecting a1,3-diyne, a secondary amine and paraformaldehyde to Mannich reaction.

Tetrahedron Lett., 3145(1979) also discloses a method for obtaining anenyne derivative by a similar method. However, in these methods, at thesame time as the formation of the desired product, a diene derivative isproduced as a by-product in substantially the same amount as the desiredproduct. Therefore, silica gel chromatography is required for theseparation, and the yield of the (E)-enyne derivatives is low.

J. Med. Chem., 27, 1539 (1984) and the sections for starting materialsin Japanese Unexamined Patent Publications No. 123177/1982, No.146580/1983, No. 208252/1983, No. 23841/1988 and No. 313753/1988disclose processes wherein an acetylene compound is lithiated withn-butyl lithium and then reacted by 1,2-addition with acrolein to obtaina secondary alcohol, and then an aqueous hydrogen bromide solution isreacted thereto to obtain a bromo derivative of an enyne, and then it isreacted with an amine. However, in these methods, the product is amixture of E:Z=3:1. In order to isolate a desired (E)-enyne amine,silica gel chromatography is required.

In Tetrahedron Lett. 29, 1509 (1989), a secondary amine is lithiated at-78° C., then propargyl bromide is reacted thereto to obtain a propargylamine derivative, which is then subjected to hydrozirconation withzirconocene chloride hydride, and then iodinated to an (E)-3-iodoallylamine derivative. tert-Butylacetylene is lithiated and then reacted withtributylstannyl chloride at -78° C. to obtaintert-butylethynyltributylstannane, which is then subjected to crosscoupling with the above-mentioned (E)-3-iodoallyl amine derivative toobtain an (E)-enyne amine derivative in good yield. However, this methodrequires n-butyl lithium and a low temperature of -78° C. for thepreparation of the propargyl amine derivative, and it also has adrawback that it requires a stoichiometric amount of such a specialreagent as zirconocene chloride hydride.

It is an object of the present invention to develop an industriallyadvantageous process for producing an enyne derivative showing stronginhibiting activities against squalene.epoxidase of Eumycetes, an enynederivative which selectively inhibits squalene.epoxidase of mammals andwhich shows strong anti-cholesterol activities and intermediates fortheir preparation.

The present inventors have conducted an extensive research to accomplishsuch an object and as a result, have found a process for producing anacetylene-conjugated allylamine derivative in good yield at a low costunder a mild reaction condition while maintaining a stereo chemicalstructure of a double bond without requiring any special installation myreacting a substituted allylamine derivative of the formula (IV) with asubstituted acetylene derivative of the formula (V) as describedhereinafter in the presence of a palladium catalyst, preferably in thepresence of a palladium catalyst, a copper salt and an organic amine oran inorganic base. The present invention has been accomplished on thebasis of this discovery.

Further, they have found a synthesis for the substituted allylaminederivative of the formula (IV) and a series of new syntheses for anenyne derivative of the formula (VII) using this substituted allylaminederivative, whereby the present invention has been accomplished.

Thus, the present invention provides:

1. A process for producing an enyne derivative of the formula: ##STR3##wherein R¹ is a hydrogen atom, a lower alkyl group, a halo lower alkylgroup, a lower alkenyl group, a lower alkynyl group or a cycloalkylgroup, R² is a hydrogen atom or a group of the formula: ##STR4## whereineach of R³, R³¹ and R³² which may be the same or different, is ahydrogen atom or a lower alkyl group, each of R⁴, R⁵, R⁴¹ and R⁵¹ whichmay be the same or different, is a hydrogen atom, a halogen atom, ahydroxyl group, a lower alkyl group or a lower alkoxy group, R⁴² is ahydroxyl group, a halogen atom, a group of the formula B--O-- (wherein Bis a projecting group for a hydroxyl group), a hydroxymethyl group, aformyl group, a carboxyl group, a lower alkoxycarbonyl group, a loweralkanoyl group, an amino group, a mercapto group or a group of theformula R⁶ --X--Y-- (wherein R⁶ is a phenyl or thienyl group which mayhave one or two substituents selected from the group consisting of ahalogen atom, a hydroxyl group, a lower alkyl group, a cyano group, alower alkoxy group and a heterocyclic group, each of X and Y which maybe the same or different, is an oxygen atom, a sulfur atom, a carbonylgroup, a group of the formula --CHR^(a) -- (wherein R^(a) is a hydrogenatom or a lower alkyl group) or a group of the formula --NR^(b) --(wherein R^(b) is a hydrogen atom or a lower alkyl group), or X and Ytogether form a vinylene group or an ethynylene group), provided thatwhen either one of X and Y is an oxygen atom, a sulfur atom or a groupof the formula --NR^(b) -- (wherein R^(b) is as defined above), theother is a carbonyl group or a group of the formula --CHR^(a) --(wherein R^(a) is as defined above), and R⁷ is a lower alkyl orcycloalkyl group which may have a hydroxyl group or a lower alkoxygroup, a phenyl group or a tri-lower alkylsilyl group, which processcomprises reacting a compound of the formula:

    Z--CH.sub.2 --CH═CH--W                                 [I]

wherein W is a halogen atom, and Z is a leaving group, with an amine ofthe formula: ##STR5## wherein R¹¹ is a hydrogen atom, a lower alkylgroup, a halo lower alkyl group, a lower alkenyl group, a lower alkynylgroup or a cycloalkyl group, and R²¹ is a hydrogen atom or a group ofthe formula: ##STR6## wherein R³, R⁴, R⁵, R³¹, R³², R⁴¹, R⁴² and R⁵¹ areas defined above, if necessary in the presence of a base, to obtain acompound of the formula: ##STR7## wherein R¹¹, R²¹ and W are as definedabove, then reacting to this compound an acetylene derivative of theformula:

    HC.tbd.C--R.sup.7                                          [V]

wherein R⁷ is as defined above, in the presence of a palladium catalyst,to obtain a compound of the formula: ##STR8## wherein R¹¹, R²¹ and R⁷are as defined above, and, if necessary, N-alkylating this compound.

2. The process for producing an enyne derivative of the formula:##STR9## wherein R¹, R² and R⁷ are as defined above, which comprisesreacting a compound of the formula: ##STR10## wherein R¹¹, R²¹ and W areas defined above, with an acetylene derivative of the formula:

    HC.tbd.C--R.sup.7                                          [V]

wherein R⁷ is as defined above, in the presence of a palladium catalyst,to obtain a compound of the formula: ##STR11## where R¹¹, R²¹ and R⁷ areas defined above, and, if necessary, N-alkylating this compound.

3. A compound of the formula: ##STR12## wherein R¹¹, R²¹ and W are asdefined above. 4. A process for producing a compound of the formula:##STR13## wherein R¹¹, R²¹ and W are as defined above, which comprisesreacting a compound of the formula:

    Z--CH.sub.2 --CH═CH--W                                 [I]

wherein W and Z are as defined above, with an amine of the formula:##STR14## wherein R¹¹ and R²¹ are as defined above.

The present invention has been accomplished based on the discovery of anindustrially advantageous process for producing enyne derivatives whichstrongly inhibit squalene.epoxidase of Eumycetes or mammals and theirintermediates.

Now, the definitions of terms used in this specification and theirspecific examples will be described.

The term "lower" is used to express that the number of carbon atoms ofthe group or compound modified with this term is at most 6, preferablyat most 4.

Accordingly, the lower alkyl group may be a linear or branched alkylgroup having from 1 to 6 carbon atoms such as a methyl group, an ethylgroup, a propyl group, an isopropyl group, a butyl group, an isobutylgroup, a sec-butyl group, a tert-butyl group, a pentyl group, anisopentyl group, a neopentyl group or a hexyl group; the halo loweralkyl group may be a halo lower alkyl group having from 1 to 6 carbonatoms such as a fluoromethyl group, a trifluoromethyl group, a2,2,2-trifluoroethyl group, a 2-chloroethyl group, a 3-fluoropropylgroup, a 2-chlorobutyl group, a 5-fluoropentyl group or 6-chlorohexylgroup; the lower alkenyl group may be a linear or branched alkenyl grouphaving from 2 to 6 carbon atoms containing one or two double bonds inthe carbon chain, such as a vinyl group, a 1-propenyl group, anisopropenyl group, an allyl group, a 1-methyl-1-propenyl group, a2-methyl-1-propenyl group, a 1-methyl-2-propenyl group, a2-methyl-2-propenyl group, a 1-butenyl group, a 2-butenyl group, a3-butenyl group, a 1,3-butadienyl group, a 2-methyl-1-butenyl group, a3-methyl-1,3-butadienyl group, a 2-ethyl-! -butenyl group, a3-methyl-2-butenyl group, a 1-pentenyl group, a 2-pentenyl group, a1,3-pentadienyl group, a 2,4-pentadienyl group, a 3-methyl-2-pentenylgroup, a 1-hexenyl group or a 2-hexenyl group; and the lower alkynylgroup may be a linear or branched alkynyl group having from 2 to 6carbon atoms containing one or two triple bonds in the carbon chain,such as an ethynyl group, a 1-propynyl group, a propargyl group, a1-butynyl group, a 2-butynyl group, a 3-butynyl group, a3-methyl-1-butynyl group, a 3,3-dimethyl-1-butynyl group, a 1-pentynylgroup, a 2-pentynyl group, a 3-pentynyl group, a 1,3-pentandiynyl group,a 1-ethynyl-2-propynyl group, a 4-methyl-2-pentynyl group or a 2-hexynylgroup. The lower alkoxy group may be a linear or branched alkoxy grouphaving from 1 to 4 carbon atoms such as a methoxy group, an ethoxygroup, a propoxy group, an isopropoxy group, a butoxy group, anisobutoxy group, a sec-butoxy group or a tert-butoxy group, and thelower alkoxycarbonyl group may be a lower alkoxy carbonyl group havingfrom 1 to 6 carbon atoms such as a methoxycarbonyl group, anethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group ora pentoxycarbonyl group. The lower alkanoyl group may be a loweralkanoyl group having from 2 to 6 carbon atoms such as an acetyl group,a propionyl group, a butyryl group, a pentanoyl group or a hexanoylgroup. The tri-tower alkylsilyl group may be a tri-lower alkylsilylgroup having from 3 to 8 carbon atoms such as a trimethylsilyl group ora tert-butyldimethylsilyl group. The halogen atom may be a fluorineatom, a chlorine atom, a bromine atom or an iodine atom. The leavinggroup for Z may be a halogen atom such as a chlorine atom, a bromineatom or an iodine atom, or an organic sulfonyloxy group such as amethanesulfonyloxy group or a p-toluenesulfonyloxy group. The cycloalkylgroup may be a cycloalkyl group having from 3 to 7 carbon atoms such asa cyclopropyl group, a cyclobutyl group, a cyclopentyl group, acyclohexyl group or a cycloheptyl group. The protecting group for ahydroxyl group represented by B may be the one which can readily beremoved by hydrolysis under an acidic or alkaline condition, such as amethoxymethyl group, a tetrahydropyranyl group, a trityl group, atert-butyldimethylsilyl group, a formyl group, an acetyl group, amethoxycarbonyl group, an ethoxycarbonyl group or a tert-butoxycarbonylgroup.

The heterocyclic group may be a 5-12-membered, preferabely 5- or6-membered heterocyclic group having from 1 to 3 hetero atoms selectedfrom the group consisting of a nitrogen atom, an oxygen atom and asulfur atom on its ring, such as a furyl group, a tetrahydrofuryl group,a pyrrolyl group, a pyrrolydinyl group, an imidazolyl group, a pyrazolylgroup, an oxazolyl group, an isoxazolyl group, a furazanyl group,thiazolyl group, an isothiazolyl group, a thiadiazolyl group, a thienylgroup, a pyridyl group, a piperidyl group, a pyrazinyl group, apyrimidinyl group, a pyridazinyl group, a piperadinyl group, amorpholinyl group, a thiomorpholinyl group, a triazinyl group, aquinolyl group, an isoquinolyl group, a phthalazinyl group, anaphthyridinyl group, a quinoxalinyl group, a quinoxalinyl group, abenzofuranyl group, a benzothienyl group, a benzoisoxazolyl group, abenzothiazolyl group or a benzofurazanyl group.

X and Y may be the same or different as described above, and eachrepresents an oxygen atom, a sulfur atom, a carbonyl group, a group ofthe formula --CHR^(a) -- (wherein R^(a) is a hydrogen atom or a loweralkyl group) or a group of the formula --NR^(b) -- (wherein R^(b) is ahydrogen atom or a lower alkyl group), or X and Y together represent avinylene group or ethynylene group, provided that either one of X and Yis an oxygen atom, a sulfur atom or the group of the formula --NR^(b)--, the other represents a carbonyl group or the group of the formula--CHR^(a) --. Specifically, the group of the formula --X--Y-- may be agroup of the formula --(CHR^(a))₂ --, --CHR^(a) O--, --OCHR^(a) --,CHR^(a) S--, --SCHR^(a) --, CHR^(a) NR^(b) --, --NR^(b) CHR^(a) --,CHR^(a) CO--, --COCHR^(a) --, --COO--, --OCO--, --COS--, --SCO--,--CONR^(b) --, --NR^(b) CO--, --CH═CH--, --C.tbd.C-- (wherein R^(a) andR^(b) are as defined above).

The palladium catalyst is a catalyst useful for a palladiumcatalyst-cross coupling reaction (Accounts of Chemical Research, 12,146-151 (1979); ditto, 15, 340-348 (1982); Angew. Chem. int. Ed. Engl.,25, 508-524 (1986)). It may be a palladium-tertiary phosphine complex,as defined hereinafter, or a combination of a palladium salt and atertiary phosphine or a combination of a palladium complex and atertiary phosphine. The palladium-tertiary phosphine complex means acomplex of zerovalent or bivalent palladium with a tertiary phosphinesuch as a trialkyl phosphine or a triaryl phosphine, and it may, forexample, be tetrakis(triphenylphosphine)palladium,bis(triphenylphosphine)palladium bromide,bis(triphenylphosphine)palladium chloride,acetoxybis(triphenylphosphine)palladium,benzylchlorobis(triphenylphosphine)palladium,tetrakis(tributylphosphine)palladium, bis(trimethylphosphine)palladiumchloride, bis(triethylphosphine)palladium chloride,bis(tripropylphosphine)palladium chloride orbis(tributylphosphine)palladium chloride. Preferred aretetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladiumbromide, bis(triphenylphosphine)palladium chloride andacetoxybis(triphenylphosphine)palladium.

The palladium salt is a salt formed by a bivalent palladium ion and anacid residue, such as palladium chloride, palladium bromide, palladiumacetate, palladium nitrate or palladium sulfate. Preferred are palladiumchloride, palladium bromide and palladium acetate.

The palladium complex means, in addition to the above palladium-tertiaryphosphine complex, other complexes of zerovalent or bivalent palladium.As such a complex, bis(phenylethylamine)palladium chloride,bis(benzonitriie)palladium chloride, bis(benzonitrile)palladium bromideor bis(acetonitrile)palladium chloride may be mentioned. Preferred arebis(benzonitrile)palladium chloride and bis(acetonitrile)palladiumchloride.

The tertiary phosphine may be triphenyl phosphine, tributyl phosphine,tripropyl phosphine, triethyl phosphine or trimethyl phosphine.Preferred is triphenyl phosphine.

The copper salt means a monovalent or bivalent copper salt such ascopper(I) chloride, copper(I) bromide, copper(I) iodide, copper(II)chloride, copper(II) bromide, or copper(II) iodide.

The organic amine may be a primary, secondary or tertiary alkylamine, oran aromatic amine, such as trimethylamine, triethylamine,diisopropylethylamine, diethylamine, diisopropyiamine, ethylamine,isopropylamine, n-butylamine, isobutylamine, pyridine,N,N-dimethylaniline or 4-dimethylaminopyridine. The inorganic salt maybe potassium hydroxide, sodium hydroxide, potassium hydrogen carbonate,sodium hydrogen carbonate, potassium carbonate or sodium carbonate.

When both or one of R¹¹ and R²¹ of the formula [VI] is a hydrogen atom,the N-alkylation means, in addition to a reaction for introducing alower alkyl group on N, a reaction for introducing a halo lower alkylgroup, a lower alkenyl group, a lower alkynyl group or a cycloalkylgroup on N as well as a reaction for introducing on N a group of theformula: ##STR15## wherein R³, R⁴, R⁵, R³¹, R³², R⁴¹, R⁴² and R⁵¹ are asdefined above.

Now, the process of the present invention will be described.

The process of the present invention comprises steps of the followingreactions, or at least two continuous steps among them. ##STR16##

The reaction of the compound of the formula [I] with the amine of theformula [II] is usually conducted by means of a suitable solvent, or theamine of the formula [II] may be used also as a solvent. The solvent tobe used here is selected from solvents which do not adversely effect thereaction. As such a solvent, an alcohol such as methanol, ethanol,propanol or isopropyl alcohol, a halogenated hydrocarbon such asdichloromethane, chloroform or trichloroethane, an aromatic hydrocarbonsuch as benzene or toluene, a ketone such as acetone or methyl isobutylketone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide,dimethyl sulfoxide, or a mixture thereof or a mixture thereof withwater, may be mentioned.

The reaction temperature is usually within a range of from -10° C. tothe boiling point of the solvent or to the boiling point of the amine,and the reaction time is usually from 30 minutes to 24 hours. However,such conditions are not necessarily limited to these ranges.

If necessary, a base may be employed. As such a base, an organic aminesuch as trimethyl amine, triethyl amine, pyridine, N,N-dimethylanilineor 4-dimethylaminopyridine, or an inorganic base such as potassiumhydroxide, sodium hydroxide, potassium hydrogen carbonate, sodiumhydrogen carbonate, potassium carbonate or sodium carbonate, may bementioned.

The coupling reaction of the allylamine derivative of the formula [IV]having a halogen atom on a double bond with the substituted acetylenederivative of the formula [V] is conducted in the presence of the abovementioned palladium catalyst, preferably in the presence of thepalladium catalyst, a copper salt and an organic amine or an inorganicsalt, if necessary by means of a suitable solvent.

The organic solvent useful for the reaction may be an alcohol such asmethanol or ethanol, a halogenated hydrocarbon such as chloroform ordichioromethane, an aromatic hydrocarbon such as benzene or toluene, anether such as diethyl ether, tetrahydrofuran or dioxane, or an aproticpolar solvent such as dimethylformamide, dimethyl sulfoxide oracetonitrile.

There is no particular restriction as to the amounts of the respectivereagents used for the coupling reaction. Preferably, however, from 1 to2 equivalent of the acetylene derivative of the formula [V] and from0.005 to 0.1 equivalent of the palladium catalyst are used perequivalent of the allylamine derivative of the formula [IV]. Further,when the palladium catalyst is other than the palladium-tertiaryphosphine complex, it is preferred to use from 0.01 to 0.2 equivalent ofa tertiary phosphine per equivalent of the compound of the formula [IV],in addition to a palladium salt or a palladium complex.

The copper salt is preferably used in an amount of from 0.005 to 0.1equivalent per equivalent of the compound of the formula [IV].

The organic amine may be used in large excess as a solvent. When anorganic amine or an inorganic base is used in an organic solvent, suchan organic amine or an inorganic base is used usually in an amount offrom 1 to 5 equivalent per equivalent of the compound of the formula[IV].

Usually, the cross coupling reaction of the compound of the formula [IV]with the compound of the formula [IV] is conducted in such a manner thatthe compound of the formula [IV], the palladium catalyst and the coppersalt are added to the organic solvent, then to this mixture, the organicamine and the compound of the formula [IV] are added preferably understirring, followed by stirring usually at a temperature of from 0° to150° C., preferably from 10° to 60° C. for from 0.5 to 24 hours.

The step for producing the compound of the formula [VII] by theN-alkylation of the compound of the formula [VI] corresponds to a stepof the N-alkylation as defined above in a case where both or one of R¹¹and R²¹ in the formula [VI] is a hydrogen atom. When R¹¹ and R²¹ areboth hydrogen atoms, the N-alkylation step may be repeated twice. Thisreaction is conducted by condensing the compound of the formula [VI]with an alkylating agent usually in a suitable solvent. The solvent tobe used for this purpose is selected from solvents which do notadversely effect the reaction. A solvent may be an alcohol such asmethanol, ethanol, propanol or isopropyl alcohol, a halogenatedhydrocarbon such as dichloromethane, chloroform or trichtoroethane, anaromatic hydrocarbon such as benzene or toluene, a ketone such asacetone or methyl isobutyl ketone, tetrahydrofuran, dioxane,acetonitrile, dimethyiformamide, dimethyl sulfoxide, or a mixturethereof or a mixture thereof with water.

The reaction temperature is usually within a range of from -10° C. tothe boiling point of the solvent, and the reaction time is usually from30 minutes to 24 hours. However, such conditions are not necessarilylimited to these ranges.

Further, if necessary, a base may be employed. As such a base, anorganic amine such as trimethylamine, triethylamine, pyridine,N,N-dimethylaniline or 4-dimethylamino pyridine, or an inorganic basesuch as potassium hydroxide, sodium hydroxide, potassium hydrogencarbonate, sodium hydrogen carbonate, potassium carbonate or sodiumcarbonate, may be mentioned.

The isolation and purification of the desired product in each of theabove steps may be conducted by conventional isolation and purificationmethods such as extraction, recrystallization or chromatography.Depending upon the desired products, they may be isolated in the form ofacid-addition salts such as hydrochlorides, sulfates or nitrates.

Now, the present invention will be described in further detail withreference to Examples and reference Examples. However, it should beunderstood that the present invention is by no means restricted to suchspecific Examples.

EXAMPLE 1 (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)propylamine hydrochloride

To a solution of 100 ml (1.21 mol) of n-propylamine in 170 ml oftetrahydrofuran was added 18.2 ml (0.198 mol) of 1,3-dichloropropene(E/Z=9/1) under ice cooling. The solution was stirred for 2 hours, and1.90 g (0.01 mol) of copper (I) iodide, 709 mg (4.0 mmol) of palladiumchloride, 2.10 g (8.0 mmol) of triphenyiphosphine and 29.3 ml (0.238mol) of tert-butylacetylene were added to the solution under icecooling. The mixture was stirred for 20 hours at room temperature, andextracted with a mixture of 100 ml of ethyl acetate and 100 ml of water.The organic layer was washed with 100 ml of water. The aqueous layerswere combined and extracted with 20 ml of ethyl acetate. A mixture of200 ml of water and 6N hydrochloric acid was then added to the combinedorganic layers to adjust to pH 2. The aqueous layer was separated. Theorganic layer was extracted with 50 ml and 20 ml of water. The aqueouslayers were combined, and washed with a mixture of 50 ml of ethylacetate and 20 ml of n-hexane. The aqueous layer was treated with 200 mlof dichloromethane and then adjusted to pH 9 with 6N sodium hydroxideaqueous solution. The organic layer was separated and the aqueous layerwas extracted with 20 ml of dichloromethane. The combined organic layerswere washed with 50 ml of a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate, and treated with17% isopropylalcohol solution of hydrogen chloride. The solvent andexcess hydrogen chloride were distilled off under reduced pressure tocrystallize. The crystalline residue was suspended with a mixture of 30ml of ethyl acetate and 50 ml of n-hexane. The crystals were collectedby filtration and then dried under reduced pressure to obtain 25.0 g(yield: 59%) of the above identified compound as slightly yellowishbrown crystalline powder.

Melting point: 190°-194° C.

IR(KBr)cm⁻¹ : 2970, 2930, 2770, 2720, 2500, 2410, 1630, 1455, 1360,1260, 960

NMR(CDCl₃)δ: 1.03(3H, t, 7 Hz), 1.22(9H, s), 1.90(2H, q, 7 Hz), 2,84(2H,bt), 3.63(2H, d, 7.5 Hz), 5.89(1H, d, 15 Hz), 6.22(1H, dt, 15 Hz, 7.5Hz), 9.71(2H, bs)

EXAMPLE 2 (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)ethylamine hydrochloride

By using 145 ml (1.79 mol) of 70% ethylamine aqueous solution instead ofn-propylamine, 255 ml of tetahydrofuran, 27.3 ml (0,296 mol) of1,3-dichloropropene (E/Z=9/1), 2.85 g (15 mmol) of copper (I) iodide,1.07 g (6.0 mmol) of palladium chloride, 3.15 g (12 mmol) oftriphenylphosphine and 45.0 ml (0.365 mol) of tert-butylacetylene, thetreatment was conducted in the same manner as in Example 1 to obtain44.4 g (yield: 74%) of the above identified compound as slightlyyellowish brown crystalline powder.

Melting point: 172°-173° C.

IR(KBr)cm⁻¹ : 2970, 2930, 2700, 2470, 2370, 1630, 1455, 1360, 1260, 970,950, 800

NMR(CDCl₃)δ: 1.22(9H, s), 1.46(3H, t, 7Hz), 3.03(2H, q, 7 Hz), 3.63(2H,d, 8 Hz), 5.91(1H, d, 16 Hz), 6.21(1H, dt, 16 Hz, 8 Hz), 9.74(2H, bs)

EXAMPLE 3 (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)methylamine hydrochloride

By using 104 ml (3.02 mol) of 40% methylamine aqueous solution insteadof n-propylamine, 85 ml of tetrahydrofuran, 9.10 ml (98.8 mmol) of1,3-dichioropropene (E/Z=9/1), 950 mg (5 mmol) of copper (I) iodide, 355mg (2 mmol) of palladium chloride, 1.05 g (4 mmol) of triphenylphosphineand 15.0 ml (0.121 mol) of tert-butylacetylene, the treatment wasconducted in the same manner as in Example 1 to obtain 12.9 g (yield:70%) of the above identified compound as off-white crystalline powder.

Melting point: 167° C.

IR(KBr)cm⁻¹ : 2970, 2770, 2720, 2440, 1470, 1460, 1440, 1360, 1270,1200, 850

NMR (CDCl₃)δ: 1.22(9H, s), 2.66(3H, s), 3.64(2}q, d, 8 Hz ), 5.92 (1H,d, 16 Hz), 6.18(1H, dt, 16 Hz, 8 Hz), 9.69(2H, bs)

EXAMPLE 4 (E)-N-(6-Methoxy-6-methyl-2-hepten-4-ynyl)ethylaminehydrochloride

To a solution of 232.4 ml (4.1 mol) of 70% ethylamine aqueous solutionin 386 ml of tetrahydrofuran was added 43.4 ml (0.47 mol) of1,3-dichloropropene (E/Z=9/1) under ice cooling. The solution wasstirred for 2 hours at the same temperature and for one hour at roomtemperature. Then, 4.65 g (24.4 mmol) of copper (I) iodide, 1.74 g (9.8mmol) of palladium chloride, 4.83 g (18.4 mmol) of triphenylphosphineand 20.0 g (0.204 mol) of 3-methoxy-3-methyl-l-butyne were added thereinunder ice cooling and the mixture was stirred at 30°-40° C. for 10hours. The solvent was distilled off under reduced pressure and theresidue was extracted with 300 ml of ethyl acetate. The organic layerwas washed with 100 ml of saturated sodium chloride aqueous solution and100 ml of 10% sodium carbonate aqueous solution, and then dried overanhydrous magnesium sulfate. The organic layer was concentrated underreduced pressure and the residue was distilled under reduced pressure toobtain 47 g of slightly yellow oil at 95° C./4 mmHg. The oil wasdissolved in 100 ml of dichloromethane and 94 ml of 23% hydrogenchloride methanol solution was added thereto to acidify, and then thesolvent was distilled off under reduced pressure. Precipitated crystalswere suspended in ether, collected by filtration, washed with ether andthen dried under reduced pressure to obtain 24.4 g (yield: 55%) of theabove identified compound as slightly purple crystalline powder.

Melting point: 139°-141° C.

IR(KBr)cm⁻¹ : 2990, 2940, 1660, 1630, 1550, 1430, 1410, 1320, 1010, 830

NMR(CDCl₃)δ: 1.45(9H, s), 1.47(3H, t, 7.5 Hz), 3.02(2H, q, 7.5 Hz),3.33(3H, s), 3.63(2H, d, 7.5 Hz), 5.95(1H, d, 15 Hz), 6.30(1H, dt, 15Hz, 7.5 Hz), 9.81(2H, bs)

EXAMPLE 5(E)-3-Chloro-N-(3-chloro-2-propenyl)-N-methylbenzo[b]thiphene-7-methanamine

To a solution of 2.62 g (10 mmol) of7-bromomethyl-3-chlorobezo[b]thiophene in 10 ml of dimethyl sulfoxidewere added 1.7 g (12 mmol) of (E)-N-(3-chloro-2-propenyl)methylaminehydrochloride and 2.07 g (15 mmol) of ground potassium carbonate. Themixture was stirred for 16 hours at room temperature, and poured into150 ml of dichloromethane. The organic layer was washed with 100 ml×2 ofwater and 50 ml of saturated sodium chloride aqueous solution, driedover anhydrous magnesium sulfate and then concentrated under reducedpressure. The residue was subjected to silica gel column chromatography(n-heptane). The desired fractions were put together and concentratedunder reduced pressure to obtain 2.12 g (yield: 74%) of the aboveidentified compound as an oil.

IR(KBr)cm⁻¹ : 3100, 3055, 2790, 1635, 1505, 1455, 1395, 1325, 1045, 930,785, 725

NMR(CDCl₃)δ: 2.24(3H, s), 3.10(2H, d, 6 Hz), 3.79(2H, s), 6.08(1H, dt,14 Hz, 6 Hz), 6.18(1H, d, 14 Hz), 7.32(1H, s), 7.34(1H, d, 8 Hz),7.43(1H, t, 8 Hz), 7.79(1H, d, 8 Hz)

EXAMPLE 6(E)-3-Chloro-N-(3-chloro-2-propenyl)-N-methylbenzo[b]thiophene-7-methanamine

To a solution of 0.22 g (1.0 mmol) of3-chloro-N-methylbenzo[b]thiophene-7-methanamine in 3 ml of dimethylsulfoxide were added 0.12 ml (1.2 mmol) of 1,3-dichloropropene (E/Z=9/1)and 0.21 g (1.5 mmol) of ground potassium carbonate. The mixture wasstirred for 17 hours at 50° C., and poured into 50 ml of ethyl acetate.The organic layer was washed with 25 ml×2 of water and 10 ml ofsaturated sodium chloride aqueous solution, dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresidue was subjected to silica gel chromatography(n-heptane→n-heptane/ethyl acetate=9/1). The desired fractions were puttogether and concentrated under reduced pressure to obtain 0.21 g(yield: 73%) of the above identified compound as an oil.

IR and NMR data of the isolated compound agreed with those of Example 5compound.

EXAMPLE 7 (E)-N-(3-Chloro-2-propenyl)-N-ethyl-3-hydroxybenzylamine

To a solution of 34.96 g (0.231 mol) of N-ethyl-3-hydroxybenzylamine in200 ml of dimethylsulfoxide were added 25.64 g (0.231 mol) of1,3-dichloropropene (E/Z=2/1) and 16.7 g (0.121 mol) of ground potassiumcarbonate under ice cooling. The mixture was stirred for 4 hours at 50°C., poured into 250 ml of ethyl acetate, washed with 200 ml×2 of waterand 200 ml of saturated sodium chloride aqueous solution, dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The residue was subjected to silica gel chromatography(n-hexane→n-hexane/ethyl acetate=9/1). The desired fractions were puttogether and concentrated under reduced pressure to obtain 26.2 g(yield: 50%) of the above identified compound as an oil.

IR(KBr)cm⁻¹ : 2970, 2820, 1600, 1590, 1460, 1270, 780, 690

NMR(CDCl₃)δ: 1.06(3H, t, 7 Hz), 2.56(2H, q, 7 Hz), 3.12(2H, d, 6.5 Hz),3.54(2H, s), 4.9(1H, bs), 6.00(1H, dt, 13 Hz, 6.5 Hz), 6.14(1H, d, 13Hz), 6.7-6.9(3H, m), 7.18(1H, t, 8 Hz)

EXAMPLE 8 (E)-N-(3-Chloro-2-propenyl)-N-propyl-3-hydroxybenzylamine

To a solution of 3.30 g (20 mmol) of N-propyl-3-hydroxybenzyiamine in 20ml of dimethyl sulfoxide were added 1.82 g (20 mmol) of1,3-dichloropropene (E/Z=2/1) and 1.38 g (10 mmol) of ground potassiumcarbonate under ice cooling. The mixture was stirred for 1.5 hours atroom temperature and for 3 hours at 50° C., poured into 70 ml of ethylacetate, washed with 50 ml×2 of water and 50 ml of saturated sodiumchloride aqueous solution, dried over anhydrous magnesium sulfate andthen concentrated under reduced pressure. The residue was subjected tosilica gel chromatography (n-hexane→n-hexane/ethyl acetate=9/1). Thedesired fractions were put together and concentrated under reducedpressure to obtain 2.29 g (yield: 48%) of the above identified compoundas an oil.

IR(KBr)cm⁻¹ : 2950, 2800, 1590, 1460, 1270, 930, 790, 690

NMR(CDCl₃)δ: 0.85(3H, t, 7 Hz), 1.51(2H, q, 7 Hz), 2.43(2H, t, 7 Hz),3.09(2H, d, 7 Hz), 3.53(2H, s), 6.2(1H, bs), 6.00 (1H, dt, 14 Hz, 7 Hz),6.12(1H, d, 14 Hz), 6.7-6.9(3H, m), 7.18(1H, t, 8 Hz)

EXAMPLE 9 (E)-N-(3-Chloro-2-propenyl)-N-ethyl-3-bromobenzylamine

To a solution of 4.28 g (20 mmol) of N-ethyl-3-bromobenzylamine in 30 mlof N,N-dimethylformamide were added 2.44 g (22 mmol) of1,3-dichloropropene and 1.70 g (12 mmol) of ground potassium carbonateunder ice cooling. The mixture was stirred for 8 hours at 60° C., pouredinto 40 ml of ethyl acetate, washed with 40 ml×2 of water and 40 ml ofsaturated sodium chloride aqueous solution, dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure. Theresidue was subjected to silica gel chromatography(n-hexane→n-hexane/ethyl acetate=9/1). The desired fractions were puttogether and concentrated under reduced pressure to obtain 3.70 g(yield: 64%) of the above identified compound as an oil.

IR(KBr)cm⁻ : 2970, 2800, 1570, 1430, 1360, 1070, 930, 780, 670

NMR(CDCl₃)δ: 1.04(3H, t, 7 Hz), 2.52(2H, q, 7 Hz), 3.09(2H, d, 7 Hz),3.54(2H, s), 5.98(1H, dt, 14 Hz, 7 Hz), 6.13(1H, d, 14 Hz), 7.1-7.6(3H,m)

EXAMPLE 10 (E)-N-(3-Chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine

To a solution of 9.84 g (57.5 mmol) of N-methyl-1-naphthalenemethanaminein 60 ml of dimethyl sulfoxide were added 5.5 ml (60 mmol) of1,3-dichloropropene (E/Z=9/1) and 8.28 g (60 mmol) of potassiumcarbonate under ice cooling. The mixture was stirred for 6 hours at roomtemperature, poured into 250 ml of ethyl acetate, washed with 150 ml×3of water and 150 ml of saturated sodium chloride aqueous solution, driedover anhydrous magnesium sulfate and then concentrated under reducedpressure. The residue was subjected to silica gel chromatography(n-hexane→n-hexane/ethyl acetate=9/1). The desired fractions were puttogether and concentrated under reduced pressure to obtain 10.86 g(yield: 77%) of the above identified compound as an oil.

IR(KBr)cm⁻¹ : 3050, 2950, 2840, 2790, 1630, 1510, 1460, 1365, 1130,1020, 930, 790, 770

NMR(CDCl₃)δ: 2.23(3H, s), 3.10(2H, d, 6.5 Hz), 3.89(2H, s), 6.06(1H, dt,13 Hz, 6.5 Hz), 6.17(1H, d, 13 Hz), 7.4-8.3(7H, m)

EXAMPLE 11 (E)-N-(3-Chloro-2-propenyl)propylamine hydrochloride

To 19.7 ml (0.24 mol) of n-propylamine was added 1.82 ml (20 mmol) of1,3-dichloropropene (E/Z=9/1) under ice cooling. The mixture was stirredfor 3 hours at the same temperature, and concentrated under reducedpressure to remove n-propylamine. The residue was treated with 50 ml ofethyl acetate and precipitated n-propylamine hydrochloride was filteredand washed with 10 ml of ethyl acetate. The filtrate and washing werecombined, washed with 20 ml of saturated sodium hydrogen carbonateaqueous solution and 20 ml of water and 20 ml of saturated sodiumchloride aqueous solution, dried over anhydrous magnesium sulfate, andthen concentrated under reduced pressure. The yellow residual oil wasdissolved in 4 ml of 23% hydrogen chloride methanol solution. Thesolvent and excess hydrogen chloride were distilled off under reducedpressure. The resulting crystals were suspended in 8 ml of diisopropylether, filtered, washed with 1 ml×2 of diisopropyl ether and then driedto obtain 2.38 g (yield: 70%) of the above identified compound asslightly yellowish brown crystalline powder.

Melting point: 216°-218° C.

IR(KBr)cm⁻¹ : 2970, 2800, 2730, 2680, 2520, 2430, 1640, 1460; 1020, 940,880, 810, 780, 750

NMR(CDCl₃)δ: 0.93(3H, t, 7 Hz), 1.63(2H, q, 7 Hz), 2.80(2H, t, 7 Hz),3.59(2H, d, 7 Hz), 6.14(1H, dr, 14 Hz, 7 Hz), 6.78(1H, d, 14 Hz),9.3(2H, bs)

EXAMPLE 12 (E)-N-(3-Chloro-2-propenyl)ethylamine hydrochloride

To 38.6 ml (0.48 mol) of ethylamine was added 3.64 ml (40 mmol) of1,3-dichloropropene (E/Z=9/1) under ice cooling. The mixture was stirredfor 4 hours at the same temperature. Thereto, 30 ml of dichloromethanewas added and the mixture was washed with 20 ml of water, dried overanhydrous magnesium sulfate, and then concentrated under atmosphericpressure. The residue was dissolved with 15 ml of 20% hydrogen chloridemethanol solution, and concentrated under reduced pressure to remove thesolvent and excess hydrogen chloride. The resulting crystals weresuspended in 6 ml of ethyl acetate, filtered and dried to obtain 4.85 g(yield: 78%) of the above identified compound as slightly yellowishbrown crystalline powder.

Melting point: 148°-149° C.

IR(KBr)cm⁻¹ : 2960, 2800, 2750, 2450, 1640, 1590, 1455, 1040, 940, 800

NMR(CDCl₃)δ: 1.47(3H, t, 7 Hz), 3.06(2H, q, 7 Hz), 3.65(2H, d, 7 Hz),6.17(1H, dt, 14 Hz, 7 Hz), 6.59(1H, d, 14 Hz), 9.76(2H, bs)

EXAMPLE 13(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanaminehydrochloride (terbinafine)

To 33 ml of tetrahydrofuran were added 5.40 g (22 mmol) of(E)-N-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine, 210 mg(1.1 mmol) of copper (I) iodide and 356 mg (0.31 mmol) of tetrakis(triphenylphosphine)palladium, and further, 4.35 ml (44 mmol) ofn-butylamine and 2.83 ml (23.1 mmol) of tert-butylacetylene under icecooling. The mixture was stirred for 17 hours at room temperature. Thereaction mixture was concentrated and the residue was subjected tosilica gel chromatography (n-hexane→n-hexane/ethyl acetate=9/1→4/1). Thedesired fractions were put together and concentrated under reducedpressure. The oily residue was dissolved in 6 ml of ethanol and 6 ml of23% hydrogen chloride methanol solution was added thereto. The solventand excess hydrogen chloride were distilled off. The resulting crystalswere suspended in diisopropyl ether, filtered, washed with diisopropylether and dried to obtain 6.41 g (yield: 89%) of the above identifiedcompound as white crystalline powder.

Melting point: 205° C.

IR(KBr)cm⁻¹ : 2970, 2440, 1465, 1410, 1360, 955, 805, 770

NMR(CDCl₃ +D₂ O)δ: 1.23(9H, s), 2.60(3H, s), 3.72(2H, d, 7.5 Hz),4.62(2H, s), 5.87(1H, d, 15 Hz), 6.37(1H, dt, 15 Hz, 7.5 Hz),7.5-8.2(7H, m)

EXAMPLE 14(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-hydroxybenzylamine

To 30 ml of tetrahydrofuran were added 4.51 g (20 mmol) of(E)-N-(3-chloro-2-propenyl)-N-ethyl-3-hydroxybenzylamine, 190.5 mg (1mmol) of copper (I) iodide and 324 mg (0.28 mmol) of tetrakis(triphenyiphosphine)palladium, and further, 3.95 ml (40 mmol) ofn-butylamine and 2.94 ml (24 mmol) of tert-butylacetylene under icecooling. The mixture was stirred for 20 hours at room temperature. Thereaction mixture was concentrated under reduced pressure and the residuewas subjected to silica gel chromatography (n-hexane→n-hexane/ethylacetate=7/3). The desired fractions were put together and concentratedunder reduced pressure to oil. The oil was cooled to crystallize and thecrystals were suspended in cooled n-hexane. The crystals were collectedby filtration and then dried to obtain 4.20 g (yield: 77%) of the aboveidentified compound as slightly yellow crystalline powder.

Melting point: 72°-74° C.

IR(KBr)cm⁻¹ : 2970, 1600; 1460, 1360, 1260, 1240, 960, 860, 800, 760

NMR(CDCl₃)δ: 1.05(3H, t, 7 Hz), 1.24(9H, s), 2.53(2H, q, 7 Hz), 3.12(2H,d, 6.5 Hz), 3.53(2H, s), 4.4(1H, bs), 5.66(1H, d, 16 Hz), 6.10(1H, dt,16 Hz, 6.5 Hz), 6.7-6.9(3H, m), 7.17(1H, t, 8 Hz)

EXAMPLE 15(E)-N-(6,6-Dimethy1-2-hepten-4-ynyl)-N-ethyl-3-hydroxybenzylamine

By using 89.8 mg (0.4 mmol) of palladium acetate and 210 mg (0.8 mmol)of triphenyiphosphine instead of tetrakis(triphenylphosphine)palladium,the treatment was conducted in the same manner as in Example 14 toobtain 4.63 g (yield: 85%) of the above identified compound as slightlyyellow crystalline powder.

Melting point, IR and NMR data of the isolated compound agreed withthose of Example 14 compound.

EXAMPLE 16(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-hydroxybenzylamine

By using 70.9 mg (0.4 mmol) of palladium chloride and 210 mg (0.8 mmol)of triphenylphosphine instead of tetrakis(triphenylphosphine)palladium,the treatment was conducted in the same manner as in Example 14 toobtain 4.51 g (yield: 83%) of the above identified compound as slightlyyellow crystalline powder.

Melting point, IR and NMR data of the isolated compound agreed withthose of Example 14 compound.

EXAMPLE 17(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-bromobenzylamine

To 10 ml tetrahydrofuran were added 1.44 g (5 mmol) of(E)-N-(3-chloro-2-propenyl)-N-ethyl-3-bromobenzylamine, 47.6 mg (0.25mmol) of copper (I) iodide and 22.4 mg (0.1 mmol) of palladium acetateand 52.5 mg (0.2 mmol) of triphenylphosphine, and further, 1.0 ml (10mmol) of n-butylamine and 0.74 ml (6 mmol) of tert-butylacetylene underice cooling. The mixture was stirred for 20 hours at room temperature,and concentrated under reduced pressure. The residue was subjected tosilica gel chromatography (n-hexane→n-hexane/ethyl acetate=20/1). Thedesired fractions were put together and concentrated under reducedpressure to obtain 1.37 g (yield: 82%) of the above identified compoundas an oil.

IR(KBr)cm⁻¹ : 2970, 2800, 1595, 1570, 1470, 1450, 1260, 1260, 960, 770,670

NMR (CDCl₃)δ: 1.05(3H, t, 7 Hz), 1.26(9H, s), 2.53(2H, q, 7 Hz),3.12(2H, d, 6.5 Hz), 3.54(2H, s), 5.68(1H, d, 16 Hz), 6.12(1H, dt , 16Hz, 6.5 Hz ), 7.1-7.6(4H, m)

EXAMPLE 18(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-propyl-3-hydroxybenzylamine

To 12.5 ml of tetrahydrofuran were added 2.00 g (8.34 mmol) of(E)-N-(3-chloro-2-propenyl)-N-propyl-3-hydroxybenzylamine, 79.4 mg(0.417 mmol) of copper (I) iodide, 37.4 mg (0.167 mmol) of palladiumacetate and 87.5 mg (0.334 mmol) of triphenylphosphine, and further,1.65 ml (16.7 mmol) of n-butylamine and 1.23 ml (10.0 mmol) oftert-butylacetylene under ice cooling. The mixture was stirred for 20hours at room temperature, and concentrated under reduced pressure. Theresidue was subjected to silica gel chromatography(n-hexane→n-hexane/ethyl acetate=19/1→9/1). The desired fractions wereput together and concentrated under reduced pressure to oil. The oil wascooled to crystallize and the crystals were suspended in cooledn-hexane. The crystals were collected by filtration and then dried toobtain 2.13 g (yield: 89%) of the above identified compound as slightlyyellow crystalline powder.

Melting point: 79°-80° C.

IR(KBr)cm⁻¹ : 2990, 2810, 1580, 1480, 1335, 1285, 1265, 1240, 980, 850,780, 750, 700, 650

NMR(CDCl₃)δ: 0.85(3H, t, 7 Hz), 1.24(9H, s), 1.50(2H, q, 7 Hz), 2.41(2H,t, 7 Hz), 3.12(2H, d, 6.5 Hz), 3.53(2H, s), 5.1(1H, bs), 5.66(1H, d, 16Hz), 6.11(1H, dt, 16 Hz, 6.5 Hz), 6.7-6.9(3H, m), 7.17(1H, t, 7.5 Hz)

EXAMPLE 19(E)-N-(6-Hydroxy-6-methyl-2-hepten-4-ynyl)-N-ethyl-3-hydroxybenzylamine

To 7.5 ml tetrahydrofuran were added 1.13 g (5 mmol) of(E)-N-(3-chloro-2-pentenyl)-N-ethyl-3-hydroxybenzylamine, 4.76 mg (0.25mmol) of copper (I) iodide, 18.0 mg (0.1 mmol) of palladium chloride and52.5 mg (0.2 mmol) of triphenylphosphine, and further, 0.99 ml (10 mmol)of n-butylamine and 0.58 ml (6 mmol) of 3-methyl-1-butyne-3-ol under icecooling. The mixture was stirred for 20 hours at room temperature. Thereaction mixture was concentrated under reduced pressure and the residuewas subjected to silica gel chromatography (n-hexane→n-hexane/ethylacetate=3/2). The desired fractions were put together and concentratedunder reduced pressure to obtain 1.07 g (yield: 78%) of the aboveidentified compound as an oil.

IR(KBr)cm⁻¹ : 3400, 2980, 2930, 2800, 1600, 1590, 1450, 1360, 1240,1160, 950, 690

NMR(CDCl₃)δ: 0.98(3H, t, 7 Hz), 1.37(9H, s), 2.40(2H, q, 7 Hz), 3.08(2H,d, 6.5 Hz), 3.40(2H, s), 5.18(1H, s), 5.63(1H, d, 15.5 Hz), 5.98(1H, dt,15.5 Hz, 6.5 Hz), 6.4-6.7(3H, m), 6.98(1H, t, 7 Hz), 9.07(1H, s)

EXAMPLE 20(E)-N-(6-Methyl-2-octen-4-ynyl)-N-ethyl-3-[3-(3-thienyl)benzyloxy]benzylamine

To a solution of 100 mg (0.25 mmol) of(E)-N-(3-chloro-2-propenyl)-N-ethyl-3-[3-(3thienyl)benzyloxy]benzylaminein 2 ml of tetrahydrofuran were added 6.0 mg (0.023 mmol) oftriphenylphosphine, 4.0 mg (0.023 mmol) of palladium chloride, 6.0 mg(0.032 mmol) of copper (i) iodide, 100 μl (1 mmol) of n-butylamine and0.5 ml (5.12 mmol) of 3-methyl-1-pentyne. The mixture was stirred for 48hours at room temperature, and concentrated under reduced pressure. Theresidue was treated with a mixture of ethyl acetate and water. Theorganic layer was separated, washed with water, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas subjected to silica gel chromatography (n-hexane→n-hexane/ethylacetate=9/1). The desired fractions were put together and concentratedunder reduced pressure. The residue was subjected to thin layerchromatography to obtain 79 mg (yield: 71%) of the above identifiedcompound as a brown oil.

IR(KBr)cm⁻¹ : 2970, 2930, 2870, 2800, 1600, 1490, 1460, 1380, 1340,1260, 1150, 1090, 1040, 960, 850, 770, 690

NMR(CDCl₃)δ: 0.98(3H, t, 7 Hz), 1.03(3H, t, 7 Hz), 1.16(3H, d, 7 Hz),1.47(2H, qui., 7 Hz), 2.49(3H, m), 3.08(2H, d, 7.5 Hz), 3.54(2H, s),5.10(2H, s), 5.64(1H, d, 16 Hz), 6.18(1H, dt, 16 Hz, 7.5 Hz),6.8-7.7(11H, m)

EXAMPLE 21(E)-N-(2-Octen-4-ynyl)-N-ethyl-3-[3-(3-thienyl)benzyloxy]benzylamine

To a solution of 100 mg (0.25 mmol) of(E)-N-(3-chloro-2-propenyl)-N-ethyl-3-[3-(3-thienyl)benzyloxy]benzylaminein 2 ml of tetrahydrofuran were added 5.6 mg(0.021 mmol) oftriphenylphosphine, 5.0 mg (0.028 mmol) of palladium chloride, 6.0 mg(0.032 mmol) of copper (I) iodide, 100 μl (1.0 mmol) of n-butylamine and464 μl (4.8 mmol) of 1-pentyne. The mixture was stirred for 24 hours at40° C. The same workup and purification as in Example 20 gave 59 mg(yield: 55%) of the above identified compound as a brown oil.

IR(KBr)cm⁻¹ : 3110, 3030, 2970, 2930, 2870, 2800, 1580, 1490, 1460,1380, 1340, 1260, 1150, 1090, 1040, 960, 880, 850, 770, 690

NMR(CDCl₃)δ: 0.99(3H, t, 7 Hz), 1.03(3H, t, 7 Hz), 1.55(2H, sex., 7 Hz),2.27(2H, t, 7 Hz), 2.50(2H, q, 7 Hz), 3.09(2H, d, 7.5 Hz), 3.54(2H, s),5.10(2H, s), 5.63(1H, d, 16 Hz), 6.10(1H, dt, 16 Hz, 7.5 Hz),6.8-7.7(11H, m)

EXAMPLE 22(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[4-(3-thienyl)-2-thienylmethyoxy]benzylamine

To 10 ml of tetrahydrofuran were added 1.01 g (2.5 mmol) of(E)-N-(3-chloro-2-propenyl)-N-ethyl-3-[4-(3-thienyl)-2-thienylmethyoxy]benzylamine,23.8 mg (0.125 mmol) of copper (I) iodide, 8.9 mg (0.05 mmol) ofpalladium chloride and 26.2 mg (0.1 mmol) of triphenylphosphine, andfurther, 0.50 ml (5.0 mmol) of n-butylamine and 0.37 ml (3.0 mmol) oftert-butylacetylene under ice cooling. The mixture was stirred for 17hours at room temperature, and extracted with a mixture of 70 ml ofethyl acetate and 30 ml of water. The organic layer was separated,washed with a mixture of 40 ml of water and 4 ml of 2N hydrochloricacid, a mixture of 40 ml of water and 6 ml of saturated sodiumbicarbonate aqueous solution and 20 ml of saturated sodium chlorideaqueous solution and then dried over anhydrous magnesium sulfate. Afterethyl acetate was evaporated under reduced pressure, the residue wastreated with 3 ml of methanol, and stirred for 17 hours under icecooling. The resulting crystals were collected by filtration, washedwith 2 ml of methanol and dried under reduced pressure to obtain 0.81 g(yield: 72%) of the above identified compound as slightly yellowishbrown crystalline powder.

Melting point: 52°-57° C.

IR(KBr)cm⁻¹ : 3100, 2960, 2920, 2800, 1610, 1580, 1480, 1440, 1360,1260, 1040, 960, 790, 750

NMR(CDCl₃)δ: 1.02 (3H, t, 7 Hz), 1.23(9H, s), 2.52(2H, q, 7 Hz),3.10(2H, d, 7 Hz), 3.55(2H, s), 5.23(2H, s), 5.66(1H, d, 16 Hz),6.10(1H, dt, 16 Hz, 7 Hz), 6.82-7.10(3H, m), 7.18-7.50(6H, m)

EXAMPLE 23(E)-3-Chloro-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylbenzo[b]thiophene-7methanaminehydrochloride

To a solution of 0.86 g (3.0 mmol) of(E)-3-chloro-N-(3-chloro-2-propenyl)-N-methylbenzo[b]thiophene-7-methanaminein 5 ml of tetrahydrofuran were added 42.6 mg (0.16 mmol) oftriphenylphosphine, 20.1 mg (0.11 mmol) of palladium chloride, 34.0 mg(0.18 mmol) of copper (I) iodide, 0.6 ml (6.1 mmol) of n-butylamine and0.5 ml (4.1 mmol) of tert-butylacetylene. The mixture was stirred for 24hours at room temperature, poured into 40 ml of ethyl acetate. Theorganic layer was separated, washed with 20 ml×2 of water, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was subjected to silica gel chromatography(n-heptane→n-heptane/ethyl acetate=5/1). The desired fractions were puttogether and concentrated under reduced pressure. The residue wastreated with 3 ml of 23% hydrogen chloride methanol solution and thesolution was concentrated. The resulting crystals were suspended inisopropylalcohol, filtered, washed with isopropylalcohol and dried toobtain 0.77 g (yield: 70%) of the above identified compound as whitecrystalline powder.

Melting point: 202° C.

IR(KBr)cm⁻¹ : 3100, 2960, 2555, 2500, 2225, 1630, 1505, 1460, 1400,1325, 1040, 965, 785, 725

NMR (CDCl₃)δ: 1.23(9H, s), 2.69(3H, s), 3.63-3.66(2H, m), 4.26-4.58(2H,m), 5.88(1H, d, 16 Hz), 6.36(1H, dt, 16 Hz, 8 Hz), 7.40(1H, s), 7.66(1H,t, 8 Hz), 7.96(1H, d, 8 Hz), 8.20(1H, d, 8 Hz), 13.2(1H, bs)

EXAMPLE 24 (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-propylaminehydrochloride

To 7.5 ml of tetrahydrofuran were added 850 mg (5 mmol) of(E)-N-(3-chloro-2-propenyl)propylamine hydrochloride, 47.6 mg (0.25mmol) of copper (I) iodide, 22.4 mg (0.1 mmol) of palladium acetate and52.5 mg (0.2 mmol) of triphenylphosphine, and further, 1.48 ml (15 mmol)of n-butylamine and 0.74 ml (6 mmol) of tert-butylacetylene under icecooling. The mixture was stirred for 20 hours at room temperature, andconcentrated under reduced pressure. The residue was subjected to silicagel chromatography (n-hexane→n-hexane/ethyl acetate=3/2). The desiredfractions were put together and concentrated under reduced pressure. Theresidue was dissolved with 15 ml of 23% hydrogen chloride methanolsolution, and the solvent and excess hydrogen chloride were distilledoff. The resulting crystals were suspended in 3 ml of a mixture of ethylacetate and diisopropyl ether (1/1), filtered, washed with 1 ml of thesame solvent and dried to obtain 780 mg (yield: 72%) of the aboveidentified compound as slightly yellowish brown crystalline powder.

Melting point, IR and NMR data of the isolated compound agreed withthose of Example 1 compound.

EXAMPLE 25 (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)ethylamine hydrochloride

To 15 ml of tetrahydrofuran were added 1.56 g (10 mmol) of(E)-N-(3-chloro-2-propenyl)ethylamine hydrochloride, 95.2 mg (0.5 mmol)of copper (I) iodide, 44.9 mg (0.2 mmol) of palladium acetate and 105 mg(0.4 mmol) of triphenylphosphine, and further, 2.97 ml (30 mmol) ofn-butylamine and 1.47 ml (12 mmol) of tert-butylacetylene under icecooling. The mixture was stirred for 18 hours at room temperature, andconcentrated under reduced pressure. The residue was subjected to silicagel chromatography (n-hexane→n-hexane/ethyl acetate=9/1→3/7). Thedesired fractions were put together and concentrated under reducedpressure. The residue was dissolved in 3 ml of 17% hydrogen chlorideisopropyl alcohol solution, and the solvent and excess hydrogen chloridewere distilled off. The resulting crystals were suspended in 20 ml of amixture of ethyl acetate and diisopropyl ether (1/3), cooled, filtered,washed with 5 ml of diisopropyl ether and dried to obtain 1.46 g (yield:72%) of the above identified compound as off-white crystalline powder.

Melting point, IR and NMR data of the isolated compound agreed withthose of Example 2 compound.

EXAMPLE 26(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[3-(3-thienyl)benzyloxy]benzylaminehydrochloride

To 2.7 ml of tetrahydrofuran were added 360 mg (0.9 mmol) of(E)-N-(3-chloro-2-propenyl)-N-ethyl-3-[3-(3-thienyl)benzyloxy]benzylamine,8.6 mg (0.045 mmol) of copper (I) iodide, 4.1 mg (0.018 mmol) ofpalladium acetate and 9.5 mg (0.036 mmol) of triphenylphosphine, andfurther, 0.18 ml (1.8 mmol) of n-butylamine and 0.135 ml (1.08 mmol) oftert-butylacetylene under ice cooling. The mixture was stirred for 24hours at room temperature, and concentrated under reduced pressure. Theresidue was subjected to silica gel chromatography(n-hexane→n-hexane/ethyl acetate=9/1). The desired fractions were puttogether and concentrated under reduced pressure to obtain 340 mg(yield: 85%) of the above identified compound as an oily free amine.

NMR(CDCl₃)δ: 1.02(3H, t, 7 Hz), 1.23(9H, s), 2.51(2H, q, 7 Hz), 3.10(2H,d, 7.5 Hz), 3.54(2H, s), 5.11(2H, s), 5.65(1H, d, 16 Hz), 6.08(1H, dt,16 Hz, 7.5 Hz), 6.9-7.8(11H, m)

The oily free amine was dissolved in 1 ml of 17% hydrogen chlorideisopropyl alcohol solution, and the solvent and excess hydrogen chloridewere distilled off. The residue was cooled to crystallize. The crystalswere suspended in 10 ml of a mixture of chloroform and n-hexane (1/10),filtered, washed with 2 ml of n-hexane and dried under reduced pressureto obtain 300 mg (yield: 89%) of the above identified compound as-whitecrystalline powder.

Melting point: 163°-165° C.

IR(KBr)cm⁻¹ : 2970, 2500, 1600, 1460, 1440, 1265, 1170, 1025, 960, 775,760, 745, 690

NMR(CDCl₃ +D₂ O)δ: 1.23(9H, s), 1.39(3H, t, 7 Hz), 3.0(2H, bm), 3.6(2H,bm), 4.08(2H, s), 5.22(2H, s), 5.81(1H, d, 16 Hz), 6.21(1H, dt, 16 Hz, 8Hz), 7.0-7.8(11H, m)

EXAMPLE 27(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanaminehydrochloride (terbinafine)

To a solution of 1.77 g (10 mmol) of 1-chloromethylnaphthalene in 10 mlof dimethyl sulfoxide were added 1.88 g (10 mmol) of(E)-N-(6,6-dimethyl-2-hepten-4-ynyl)methylamine hydrochloride and 1.66 g(12 mmol) of potassium carbonate under ice cooling. The mixture wasstirred for 16 hours at room temperature, poured into 200 ml of ethylacetate, washed with 100 ml×2 of water, a mixture of 80 ml of water and10 ml of 2 N hydrochloric acid, and 50 ml of saturated sodium chlorideaqueous solution respectively, dried over anhydrous magnesium sulfateand concentrated under reduced pressure to crystallize. The crystalswere suspended in 10 ml of ethyl acetate, cooled, filtered and driedunder reduced pressure to obtain 2.95 g (yield: 90%) of the aboveidentified compound as off-white crystalline powder.

Melting point, IR and NMR data of the isolated compound agreed withthose of Example 13 compound.

EXAMPLE 28(E)-3-Chloro-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylbenzo[b]thiophene-7-methanaminehydrochloride

To a solution of 0.34 g (1.3 mmol) of7-bromomethyl-3-chlorobenzo[b]thiophene in 3 ml of dimethyl sulfoxidewere added 0.246 g (1.31 mmol) of(E)-N-(6,6-dimethyl-2-hepten-4-ynyl)methylamine hydrochloride, and 0.27g (1.95 mmol) of potassium carbonate under ice cooling. The mixture wasstirred for 19 hours at room temperature, poured into 40 ml ofdichloromethane, washed with 30 ml×2 of water, and adjusted to pH 2 with25 ml of water and 2N hydrochloric acid. The organic layer wasseparated, washed with 20 ml of saturated sodium chloride aqueoussolution, dried over anhydrous magnesium sulfate, concentrated underreduced pressure and cooled to crystallize. The crystals were suspendedin isopropylalcohol, filtered, washed with isopropyl alcohol and driedto obtain 0.37 g (yield: 77%) of the above identified compound as whitecrystalline powder.

Melting point, IR and NMR data of the isolated compound agreed withthose of Example 23 compound.

REFERENCE EXAMPLE 1(E)-N-(3-chloro-2-propenyl)-N-ethyl-3-[3-(3-thienyl)benzyloxy]benzylamine

To a solution of 280 mg (1.24 mmol) of(E)-N-(3-chloro-2-propenyl)-N-ethyl-3-hydroxybenzyiamine in 2.5 ml oftetrahydrofuran was added 74.4 mg (1.86 mmol) of 60% oily sodium hydrideunder ice cooling. The mixture was stirred for 20 minutes at roomtemperature, ice-cooled, treated with a solution of 333 mg (1.24 mmol)of 3-(3-thienyl)benzyl mesylate in 2.5 ml of dimethylformamide, andstirred for 1.5 hours at room temperature. The reaction mixture waspoured into 40 ml of ethyl acetate, washed with 20 ml×2 of water and 20ml of saturated sodium chloride aqueous solution, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas subjected to silica gel chromatography (n-hexane→n-hexane/ethylacetate=9/1). The desired fractions were put together and concentratedunder reduced pressure to obtain 460 mg (yield: 93%) of the aboveidentified compound as an oil.

IR(KBr)cm⁻¹ : 2970, 2925, 1595, 1580, 1485, 1460, 1260, 1150, 1035, 770,690

NMR(CDCl₃)δ: 1.04(3H, t, 7 Hz), 2.52(2H, q, 7 Hz), 3.09(2H, d, 7 Hz),3.56(2H, s), 5.12(2H, s), 5.98(1H, dt, 7 Hz, 14 Hz), 6.11(1H, d, 14 Hz),6.8-7.7(11H, m)

REFERENCE EXAMPLE 2(E)-N-(3-chloro-2-propenyl)-N-ethyl-3-[4-(3-thienyl)-2-thienylmethoxy]benzylamine

To a solution of 2.26 g (10 mmol) of(E)-N-(3-chloro-2-propenyl)-N-ethyl-3-hydroxybenzylamine in 14 ml oftetrahydrofuran was added 0.48 g (12 mmol) of 60% oily sodium hydrideunder ice cooling. The mixture was stirred for 10 minutes at roomtemperature, ice-cooled, treated with a solution of 2.59 g (10 mmol) of2-bromomethyl-4-(3-thienyl)thiophene in 10 ml of dimethylformamide, andstirred for 2 hours at room temperature. The reaction mixture was pouredinto 150 ml of ethyl acetate, washed with 100 ml×2 of water and 50 ml ofsaturated sodium chloride aqueous solution, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas subjected to silica gel chromatography (n-heptane/dichloromethane).The desired fractions were put together and concentrated under reducedpressure to obtain 3.11 g (yield: 77%) of the above identified compound.

IR(KBr)cm⁻¹ : 3100, 2960, 2920, 2800, 1600, 1580, 1480, 1440, 1370 1260,1150, 1030, 840, 780, 740

NMR(CDCl₃)δ: 1.04(3H, t, 7 Hz), 2.53(2H, q, 7 Hz), 3.09(2H, d, 7 Hz),3.54(2H, s), 5.22(2H, s), 6.00(1H, dt, 7 Hz, 14 Hz), 6.11(1H, d, 14 Hz),6.84-7.12(3H, m), 7.20-7.50(6H, m)

We claim:
 1. A compound of the formula: ##STR17## wherein R¹¹ ishydrogen, lower alkyl, haloloweralkyl, lower alkenyl, lower alkynyl orcycloalkyl; R²¹ is a group of the formula: ##STR18## wherein each of R³,R³¹, and R³² which may be the same or different, is a hydrogen atom or alower alkyl group, each of R⁴, R⁵, R⁴¹ and R⁵¹, which may be the same ordifferent, is a hydrogen atom, a halogen atom, a hydroxyl group, a loweralkyl group or a lower alkoxy group, R⁴² is a hydroxyl group, a halogenatom, a group of the formula R⁸ --O-- wherein R⁸ is a protecting groupfor a hydroxyl group, a hydroxymethyl group, a formyl group, a carboxylgroup, a lower alkoxycarbonyl group, a lower alkanoyl group, an aminogroup, a mercapto group or a group of the formula R⁶ --X--Y-- wherein R⁶is a phenyl or thienyl group which may have one or two substituentsselected from the group consisting of a halogen atom, a hydroxyl group,a lower alkyl group, a cyano group, a lower alkoxy group, a furyl group,a tetrahydrofuryl group, a pyrrolyl group, pyrrolydinyl group, animidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolylgroup, a furazanyl group, a thiazolyl group, an isothioazolyl group, athiadiazolyl group, a thienyl group, a pyridyl group, a piperidyl group,a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, apiperadinyl group, a morpholinyl group, a thiomorpholinyl group, atriazinyl group, a quinolyl group, an isoquinolyl group, a phthalazinylgroup, a naphthyridinyl group, a quinoxalinyl group, a quinazolinylgroup, a benzofuranyl group, a benzothienyl group, a benzoisoxazolylgroup, a benzothiazolyl group and a benzofurazanyl group, each of X andY which may be the same or different, is an oxygen atom, a sulfur atom,a carbonyl group, a group of the formula --CHR⁸ -- wherein R^(a) is ahydrogen atom or a lower alkyl group or a group of the formula --NR^(b)wherein R^(b) is a hydrogen atom or a lower alkyl group, or X and Ytogether form a vinylene group or an ethynylene group, provided thatwhen either one of X and Y is an oxygen atom, a sulfur atom or a groupof the formula --NR^(b) wherein R^(b) is as defined above, the other isa carbonyl group or a group of the formula --CHR⁸ -- wherein R^(a) is asdefined above, and R⁷ is a lower alkyl or cycloalkyl group which mayhave a hydroxyl group or a lower alkoxy group, a phenyl group or atri-lower alkylsilyl group; and W is chlorine or bromine.